H5N1 facts, not fear

25 January 2012

Peter Palese and Taia Wang have written a compelling article that uses scientific facts to address the controversy over publication of research involving transmission of avian influenza H5N1 in ferrets. In response to calls in the media to destroy the viruses, curtail the research, and protect the public from frightening research, they write that “fear needs to be put to rest with solid science and not speculation”.

The authors begin with the facts: they indicate that the object of ferret-to-ferret passage of avian H5N1 influenza virus was to determine whether sustainable aerosol transmission could be achieved in this animal model. The finding that transmission in ferrets is conferred by a small number of mutations emphasizes the need for continued surveillance of H5 viruses and development of vaccines and antivirals.

Are these studies relevant to humans?

Ferrets are quite susceptible to infection with influenza viruses. However, it is not clear that all virus strains that replicate in and transmit between ferrets necessarily do so in humans. Ferrets are also more likely than humans to have disseminated, multiorgan influenza disease including neurological sequelae….one cannot directly extrapolate from the data to make predictions about humans.

Under the heading ‘fear’, they address the heart of this controversy, the notion that the fatality rate for human H5 infections is greater than 50%:

…in order for a case to be confirmed by WHO, a person must have an acute, febrile respiratory illness with known H5 exposure in the 7 days preceding and have molecular confirmation of H5 infection by a WHO approved laboratory. This definition does not allow for asymptomatic infections and essentially requires that a person actively seek medical help at a hospital that is equipped to draw samples and ship them to an approved laboratory….it seems unlikely that even a small fraction of the total number of infected cases has been accounted for under the WHO surveillance system.

They also review seroevidence in humans for H5 infections:

Of the 10 largest studies of which we are aware…eight report rates ranging from 0.2% to 5.6%….even if only a low percentage of the rural population is asymptomatically/subclinically infected, the case fatality rate that is offered by the WHO – and that is driving this controversy – is likely orders of magnitude too high.

The authors believe that selection of these papers for redaction by the National Science Advisory Board for Biosecurity appears arbitrary, considering what has been published on influenza in the past:

In 2005, the complete sequences for the 1918 pandemic influenza virus were published…in 2006, both Science and Nature published reports of specific mutations that enable the H5 viral hemagglutinin to bind human, rather than avian tissues. In 2012, a report from the CDC that bears striking resemblance, in principle, to the works by Fouchier and Kawaoka was already published in Virology: it describes mutations in an H5N1 virus that confer airborne transmissibility between ferrets.

Finally the address the question: Could the data from these two papers realistically be used to generate an H5N1 biologic weapon?

It would be feasable to test transmissibility in non-human primates. That would probably give an answer of the risk to humans. I would bet a nickel on it transmitting efficiently in primates and humans.

As to the arguments about the probable case fatality rate, any novel influenza virus that can reproduce and spread in the population is going to cause harm to a lot of people, especially those with “risk factors” for severe illness. That is a given, no matter how “mild”, the average symptoms are in healthy young people.

1918 flu caused an increase in the overall mortality rate in the United States of 2.5%, which is considered to be huge, and its effect is seen as the only dip in graph of increasing human life expectancy that occurred in the 20th century. The 1957 pandemic (where only the HA and NA genes, rather than the whole virus, were novel to the population) caused 0.9% excess mortality in the U.S. It’s unreasonable to think that an efficiently transmissible virus would have a mortality rate of 50 per cent, while still maintaining a high attack rate. People would be so sick and be incapacitated so quickly that the virus could not spread efficiently in the community. But any virus causing even a half a percent of case fatalities is still a deadly pandemic tha would kill millions of people.

The only consolation is that any pandemic H5 virus will probably be antigenically similar enought to the H5 vaccine strains that our vaccine stockpile will be useful. But this lab data shows that we need to do more surveillance on wild H5N1 viruses, for example to monitor antigenic drift, especially in regions of emergence in the world. I don’t think arguments over how good a model ferrets are are much use. Ferrets are a good model for SOME aspects of flu pathogenesis and transmission, but not they are not perfect. All this controversy could damage our efforts to boost our limited knowledge of H5N1 strains in the wild, by restricting work only to the highest containment labs.